The cerebral cortex encompasses several major regions that are involved in higher functions such as thought, feelings, memory and planning. Monoamines, such as dopamine, norepinephrine and serotonin, are important as neurotransmitters for mammalian cortical function. The ascending serotonergic and noradrenergic pathways innervate virtually all regions of the brain including the cerebral cortex. The dopaminergic neurons of the CNS have more distinct projections, including the meso-cortical pathway primarily innervating the frontal cortex, in addition to a number of specific subcortical pathways. Primary or secondary dysfunctions in the activity of the monoamine pathways innervating the cerebral cortex lead to aberrations of the activity at cortical dopamine, norepinephrine and serotonin receptors and subsequently to manifestations of psychiatric and neurological symptoms.
The monoamines of the cortex modulate several aspects of cortical functions controlling affect, anxiety, motivation, cognition, attention, arousal and wakefulness. Thus, the catecholamines dopamine and norepinephrine exert strong influence on the frontal cortical areas, the integrity of which is essential for the so-called executive cognitive functions, related to e.g. attention, planning of actions and impulse control. Norepinephrine is a major part in the circuitry regulating anxiety and fear and is thus believed to be dysregulated in anxiety disorders such as panic disorders, generalized anxiety disorder (GAD) and specific phobias. Concerning mood and affective functions, the usefulness of compounds facilitating particularly norepinephrine and serotonin neurotransmission in the treatment of depression and anxiety has strongly contributed to the widely-accepted concept that these neuro-transmitters are both involved in the regulation of affective functions.
Hamon et al. (Prog Neuro-Psychopharm & Bio Psych, 2013, 45, 54-63) discloses that compounds specifically affecting the transmission of monoamines, more precisely norepinephrine, dopamine and serotonin, are successfully used to alleviate the affective, cognitive, or attentional symptoms in patients suffering from e.g. depression, anxiety and attention deficit hyperactivity disorder (ADHD). In addition, Arnsten (Biol Psych, 2011, 69(12); 89-99) discloses that all current pharmacological treatments for ADHD facilitate catecholamine transmission. Furthermore, Wang (Front Cell Neurosci, 2015, 9; 1-23) discloses that modulation of monoaminergic transmission has been suggested as a promising principle for the treatment of autism spectrum disorders.
Trillo et al. (Neurosci & Biobehav Rev, 2013, 37; 1363-79) discloses that in Alzheimer's disease, progressive degeneration of ascending monoamine systems have been linked to cognitive as well as non-cognitive symptoms, and pharmacological interventions leading to enhanced monoamine transmission have been suggested as a strategy both for symptomatic and disease-modifying treatments of Alzheimer's disease.
Furthermore, the monoamine systems in the cortex are known to be directly or indirectly involved in the core symptoms of schizophrenia. It has been proposed that this disorder emerges as various pathological etiologies converge upon cortical synaptic processes leading to dysregulation of the cortical micro-circuitry, which is clinically manifested as the symptoms of schizophrenia (Harrison et al., Mol Psych, 2005, 10; 40-68). This cortical micro-circuitry is regulated by several neurotransmitters, including glutamate, GABA, and dopamine. It has further been proposed that pharmacological enhancement of cortical dopamine transmission could restore the function of this microcircuitry, providing a useful strategy for improved treatment of schizophrenia (Abi-Dargham et al., Eur Psych, 2005, 20; 15-27).
WO 2004/113297 discloses aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors. EP 2754653 discloses azetidine derivatives and their use as monoamine neurotransmitter re-uptake inhibitors.